ACCOMPLISHMENTS: Our work to date has emphasized the human CYP2C subfamily. CYP2C9, CYP2C19 and CYP2C19 have been shown to be polymorphic. CYP2C19 metabolizes the antiulcer drug omeprazole, the anticonvulsant mephenytoin, valium, certain barbiturates, activates certain antimalarials, and sulfoxidizes the pesticide phorate. We have identified 9 mutant alleles and two wild-type alleles. Two new mutant alleles include a mutation in the donor splice site of intron five and a second allele consists of an amino acid substitution in exon 3 which decreases catalytic activity by 90%. A defective CYP2C9*3 allele was found in an individual who was a PM for the metabolism of phenytoin and the antidiabetic glipizide, CYP2C9*3 was also found to be defective in vitro in the metabolism of the diuretic torsemide and the antiinflammatories diclofenac and flurbiprofen, naproxen, and proxicam and diclofenac using recombinant enzymes /and human liver microsomes. Testing of two presumed wild-type alleles CYP2C19*1A and CYP2C19*1B showed both had similar catalytic activity in a recombinant cDNA expression system. When tested in population studies, CYP2C19*1A was the rarer of the two wild-type alleles (comprising ~5% of alleles in Caucasians and Chinese) while CYP2C19*B comprised 81% of Caucasian alleles and 50% of Asian alleles where defective metabolism is more prevalent). Linkage analysis in both Caucasians and Chinese indicated that the rarer wild-type CYP2C19*1A allele was linked to a defective allele of CYP2C9 (2C9*3) responsible for defective metabolism of tolbutamide, glipizide and phenytoin. CYP2C19*4 allele (defect in the initiation codon) was found only on a haplotype which included the proposed defective allele CYP2C9*2, but not vice versa indicating that CYP2C19*4 arose at a later time. A cDNA for canine CYP2E1 was isolated and two allelic variants identified, a genetic test devised, and the cDNAs are being tested in a recombinant enzyme. The dog is an important laboratory animal for drug studies. - CYP3C19, genetic, polymorphic, metabolizers